| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to Severely Active Ulcerative Colitis |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of ozanimod in pediatric subjects with moderately to severely active UC (3-component Mayo Score: clinical remission, Week 52) |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the efficacy of ozanimod in pediatric subjects with moderately to severely active UC (3-component Mayo Score: clinical remission, Week 10)
Evaluate the efficacy of ozanimod in pediatric subjects with moderately to severely active UC (3-component Mayo Score: clinical response, Week 52)
Evaluate the efficacy of ozanimod in pediatric subjects with moderately to severely active UC (3-component Mayo Score: clinical response, Week 10)
Evaluate symptomatic remission
Evaluate time to achieve symptomatic remission
Evaluate endoscopic improvement by Mayo Endoscopy Score
Evaluate corticosteroid-free remission
Evaluate the safety and tolerability of 2 doses of ozanimod in pediatric subjects w/moderately-severely active UC
Characterize the pharmacokinetics of 2 doses of ozanimod and its major active metabolites in pediatric subjects with moderately-severely active UC
Evaluate the pharmacodynamic effects of 2doses of ozanimod in pediatric subjects w/moderately-severely active UC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 2 and < 17 years of age, inclusive, (for the assigned cohort) at the time of informed
consent/assent.
Note: Subjects with a weight below the 5
th percentile for age, should be discussed with
the Medical Monitor prior to enrollment.
2. One or both parent(s) or legal guardian(s) understands and voluntarily signs informed
consent prior to any study-related assessments or procedures (as required by national or
local regulations).
- Assent from subjects will also be obtained in an age-appropriate manner in
conjunction with applicable local regulations. Written assent templates, appropriate
for relevant age ranges, will be made available to clinical study sites.
3. Willing and able to adhere to the study visit schedule and other protocol requirements
including swallowing a capsule (until a sprinkle formulation of ozanimod is available as
described in Section 7.1).
4. Have had UC diagnosed prior to the Screening Visit. The diagnosis should be confirmed
by clinical and endoscopic evidence and corroborated by a histopathology report (note:
histopathology may be performed during endoscopy at Screening if no prior report is
readily available).
5. Evidence of UC extending beyond the rectum, as determined by baseline endoscopy
(flexible sigmoidoscopy or colonoscopy)
6. Has moderately to severely active UC, defined as a 4-component Mayo Score ≥ 6 and
≤ 12 at the time of screening and day 1, including the following: Mayo Endoscopy Subscore ≥ 2,
Rectal Bleeding Score ≥ 1, and Stool Frequency Score ≥ 1.
7. Has had an inadequate response, loss of response to, or is intolerant to at least 1 of the
following treatments for UC (Appendix B):
a. oral aminosalicylates (eg, mesalamine, sulfasalazine, olsalazine, balsalazide) (N/A in France)
b. systemic corticosteroids (eg, oral prednisone, budesonide MMX, IV corticosteroids)
c. immunomodulators (eg, AZA, 6-MP, cyclosporine, MTX)
d. biologic therapy (eg, abatacept, infliximab, etanercept, adalimumab, anakinra,
rituximab, vedolizumab, and golimumab)
e. other systemic immunomodulatory treatments for UC, such as tofacitinib
Note: criterion 7b-7e are N/A in Germany
8. Subjects may concurrently receive treatment with oral 5-ASAs, or with prednisone or
equivalent (≤ 0.5 mg/kg/ day up to 20 mg/day) or beclomethasone < 5mg/day.
- If on oral 5-ASAs, the dose must have been stable for at least 3 weeks prior to
screening endoscopy = baseline .
- If on corticosteroids, the dose must have been stable for at least 2 weeks prior to
screening endoscopy and must remain stable through the first 5 weeks of treatment
(ie, until the Week 5 study visit).
-If discontinuing corticosteroids (e.g. MMX), subject must taper as described in Section 8.1.1.
9. Inclusion criterion 9 is not applicable for protocol amendment 2.0.
10. Must have documentation of vaccinations per standard immunization schedule including
complete Varicella vaccination at least 30 days prior to randomization. (VZV and IgG +ve)
11. Females of childbearing potential (FCBP)1 must agree to practice a highly effective
method of contraception2
throughout the study until completion of the 90-day Safety
Follow-up Visit. Highly effective methods of contraception are those that alone or in
combination result in a failure rate of a Pearl index of less than 1% per year when used
consistently and correctly. Selection of contraceptive methods should be based on those
available/approved as per national or local practice. Acceptable methods of birth control
in the study are the following:
- combined hormonal (estrogen and progestogen containing) contraception, which may
be oral, intravaginal, or transdermal
- progestogen-only hormonal contraception associated with inhibition of ovulation,
which may be oral, injectable, or implantable
- placement of an intrauterine device (IUD)
- placement of an intrauterine hormone-releasing system (IUS)
- bilateral tubal occlusion
- complete sexual abstinence ([defined as refraining from heterosexual intercourse]
reliability to be evaluated based on the preferred and usual lifestyle of the subject)
- Periodic abstinence (calendar, symptothermal, post-ovulation methods),
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method |
|
| E.4 | Principal exclusion criteria |
Cardiovascular, hepatic, neurological, pulmonary, ophthalmological, endocrine, psychiatric, or other major systemic disease making implementation of the protocol or interpretation of the study difficult or that would put the subject at risk by participating in the study
Crohn’s disease, indeterminate colitis or the presence or history of a fistula consistent with Crohn’s disease or microscopic colitis, radiation colitis or ischemic colitis
+ve for toxin producing Clostridium difficile or PCR exam of stool. If +ve, subjects may be rescreened after appropriate treatment and retested no earlier than 7 days after treatment completion
+ve examination for pathogens. If positive, subjects may be treated and rescreened
History of treatment with topical rectal 5-aminosalicylic acid or topical rectal steroids within 2 weeks of Screening endoscopy or anti-motility medications
Apheresis within 2 weeks of randomization
Delayed growth or pubertal development and who will not maintain a stable dose of corticosteroids through Week 5
Pregnancy (also on day 1), lactation, or positive serum β-hCG during Screening
History or presence of: Structural cardiac disease, Cardiac events or diseases that predispose to cardiac complications, Prolonged QT interval corrected for heart rate using Fridericia’s formula>450 msec for both genders, or additional risk for QT interval prolongation, resting HR < 55 bpm in subjects 12-17 years old, resting HR < 65 bpm in subjects 6-11 years old, or resting HR < 75 bpm in subjects 2-5 years old. Subjects allowed one recheck per Visit, untreated sleep apnea
History of DM type 1, or uncontrolled DM type 2 glycosylated hemoglobin (HbA1c > 9%) or is a diabetic subject with significant comorbid conditions
History of uveitis within the last year prior or at Screening, or history or evidence of retinal disease
Subject has any known active bacterial, viral, fungal, mycobacterial infection, or any major episode infection that required hospitalization or treatment with intravenous antibiotics within 30 days of Screening or oral antibiotics within 14 days of screening
In the case of prior SARS-CoV-2 infection, symptoms must be resolved and based on Investigator assessment, there are no sequelae that would place the subject at a higher risk of receiving investigational treatment
Recurrent or chronic infection, recurrent urinary tract infections are allowed, there should also be documented evidence of surveillance for dysplasia for all subjects with left-sided colitis of > 12 years’ duration and total or extensive colitis of > 8 years’ duration.
History of cancer
History of or currently active primary or secondary immunodeficiency, or subjects with known genetic disorders as a cause for colitis
ECG showing clinically significant abnormality
Serum creatinine > 1.4 mg/dL for females, or > 1.6 mg/dL for males
Liver function impairment; or, persisting elevations of alanine aminotransferase or aspartate aminotransferase > 2x upper limit of normal; or direct bilirubin > 1.5x UL
Platelet < 100,000/μL
Hemoglobin 7 < 8 g/dL
Neutrophil < 1500/μL
Absolute white blood < 3500/μL
ALC < 800/μL
Stool positive for pathogens
Pulmonary function test measurements: Forced expiratory volume at 1 second or a forced vital capacity < 70% of predicted values, Hypersensitivity to active ingredients or excipients of ozanimod
Treated with biological or investigational agent, including for SARS-CoV-2, within 4 weeks of that agent prior to the first dose of IP. Undetectable drug levels on therapeutic drug monitoring assays may be utilized
Received live attenuated vaccine within 4 weeks prior to the first dose of IP. Non-live vaccinations can be administered during the study
Any previous treatment with lymphocyte-depleting therapies
Treatment with D-penicillamine, leflunomide, or thalidomide within 8 weeks of first dose of IP
Previous treatment with natalizumab, fingolimod, or other S1P receptor modulators
History of treatment with IV immune globulin, or plasmapheresis within 3 months prior to first dose of IP
Previous treatment with oral cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 16 weeks of initiation of Screening
Planned concurrent treatment with immunomodulatory after randomization. Subjects receiving AZA, 6-MP, or MTX at screening must discontinue treatment with these agents prior to first dose of IP
Chronic nonsteroidal anti-inflammatory drug use (occasional use of NSAIDs, acetaminophen and aspirin PRN or up to 325 mg/day is permitted)
Receiving treatment with Class Ia or Class III anti-arrhythmic drugs or with 2 or more agents in combination known to prolong PR interval
Received cholestyramine or other drugs interfering with enterohepatic circulation within 3 weeks of Screening
Receiving treatment with:
At randomization:
Inducers
2 weeks prior to randomization:
Monoamine oxidase inhibitors |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of subjects who achieve clinical remission, defined as all the following:
• Mayo Endoscopy Subscore (MES) ≤ 1
• Rectal Bleeding Subscore (RBS) = 0
• Stool Frequency Subscore (SFS) ≤ 1, with a decrease of ≥ 1 point from Baseline SFS
Proportion of subjects who achieve histological remission, defined as the following:
- Geboes index score < 2.0
- Robarts Histopathology Index (RHI) ≤ 3, with subscores of 0 for both lamina propria
neutrophils and neutrophils in the epithelium
Early Discontinuation: Starting at Week 5 or later if either one of the following criteria are met
at 2 consecutive visits that are at least 2 weeks apart:
- Partial Mayo score is ≥ 7 and is the same or worse than baseline, AND rectal bleeding and
stool frequency are not improved from baseline
- Partial Mayo score is 6 and worse than baseline, AND rectal bleeding and stool frequency
are not improved from baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1/Proportion of subjects who achieve clinical response defined as all the following:
• Decrease from Baseline in the 3-component Mayo score of at least 2 points and at least 35%
• Decrease in RBS of at least 1 point OR absolute RBS ≤ 1
2/Proportion of subjects who achieve clinical remission defined as all the following:
• MES ≤ 1
• RBS = 0
• SFS ≤ 1, with a decrease of ≥1 point from Baseline SFS
3/Proportion of subjects who achieve symptomatic improvement of UC, defined as all the following:
• RBS = 0
• SFS ≤ 1
• Decrease in SFS of ≥ 1 from Baseline
4/Proportion of subjects who achieve endoscopic improvement, defined as MES ≤ 1
5/Proportion of subjects who achieve corticosteroid-free remission at Week 52, defined as all the following:
• Did not receive steroids for ≥ 12 weeks prior to Week 52
• Achieved clinical remission defined by the 3-component Mayo score
6/Secondary – Safety and Tolerability
Number and proportion of subjects experiencing AEs, SAEs, AEs leading to discontinuation from treatment, and AEs of interest (AEIs)
7/Secondary - Pharmacokinetics
Steady state systemic exposure of ozanimod and CC112273
8/Secondary – Pharmacodynamics
Absolute and percent change from baseline in ALC
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1/Week 10 and week 52
2/Week 10
3/Week 10 and week 52
4/Week 10 and week 52
5/Week 52
6/throughout the study
7/Week 18 and throughout the study
8/Week 10 and week 52 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Israel |
| Japan |
| Russian Federation |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Netherlands |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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